This invention relates in general to the field of medicine and to therapeutic methods for treating disruption of neural function resulting from damage to the central nervous system (CNS), and more particularly to methods for restoring motor and sensory function in subjects suffering from CNS damage.
Damage to the mammalian CNS can produce devastating physical impairment, and incur many added medical complications that in themselves can be life-threatening. CNS damage can result, for example, from spinal cord injury (“SCI”), which typically involves a complete or partial severance of a region of the spinal cord in an auto or other accident, or from a stroke-induced lesion. SCI can also be the result of a chronic disease process such as multiple sclerosis or a cancerous tumor. Acute trauma and chronic disease processes such as multiple sclerosis can also produce lesions elsewhere in the CNS that result in dramatic impairment of sensory or motor function, or both.
Besides impairment of motor and sensory function, additional medical consequences of CNS damage almost always arise. For example, medical complications resulting from substantial motor impairment include muscular atrophy, loss of bone mineral content, decubitus ulcers, urinary tract infections, muscle spasticity, impaired circulation, and reduced heart and lung capacity.
The American Spinal Injury Association (“ASIA”) has developed international standards for examining and reporting the severity of spinal cord injury (“SCI”). Table 1 presents ASIA's five grades of spinal cord function, A to E, where E is normal. The ASIA Grade A describes individuals with the least remaining function. Such patients have little hope for recovery. Least than 1% of those with no muscle activity in the lower extremities 1 month after injury learn to walk again, and only 10% recover enough function to be reclassified as ASIA B or better. Approximately 90% of patients remain classified as ASIA Grade A.
TABLE 1ASIA'S international standards for classifying SCIGradeDescriptionAComplete. No sensory or motor function preserved insacral segments S4-S5BIncomplete. Sensory but not motor function preservedbelow the neurologic level and extending throughsacral segments S4-S5CIncomplete. Motor function preserved below theneurologic level; majority of key muscle have agrade < 3DIncomplete. Motor function preserved below theneurologic level; majority of key muscles have agrade > 3ENormal motor and sensory function
Patients with SCI are often told that improvement or recovery occurs largely in the first 6 months after injury and is complete by 2 years. Indeed, the literature does not provide a single example of an individual with an ASIA Grade A SCI who recovered by more than one grade 2 years after injury. Some delayed recoveries occur, but the timeframe is typically between 1 and 6 months after injury for large improvements. Such recoveries are most common when an accompanying head injury impedes initial progress. Small improvements can occur after periods longer than 2 years but typically occur in individuals with incomplete injuries.
Some number of individuals with ASIA Grade A SCI might have at least some functional connections across the SCI lesion. Indeed, it is rare for the cord to be completely severed by spinal trauma unless a gunshot or knife attack causes the wound. Studies performed in the 1950s indicate that limited preservation of white matter across the SCI lesion can sustain substantial spinal cord function. Preservation of less than 10% of the normal axon complement in the cat spinal cord can support walking, although this should not be viewed as the optimal requirement. Moreover, detailed anatomical postmortem studies of chronic SCI in humans reveal that small residual connections across the lesion can preserve some function. For example, one individual with ASIA Grade C SCI had retained only 1.17 mm2 of white matter at the level of the lesion. Another patient with some preserved motor function below the level of a cervical injury had only 3175 corticospinal axons—less than 8% of the number (41,472) found in normal controls.
A decade ago, the adult central nervous system (“CNS”) was thought to be incapable of regeneration. Rehabilitation focused primarily on the immediate post-injury phase, when patients were still in the hospital, and aimed to maximize existing function and minimize complications. Although these goals are still important, the concept of spontaneous regeneration has emerged.
Current treatments for SCI are both limited and controversial. Administration of methylprednisolone within 8 hours of traumatic injury was one of the first drug therapies to receive support. Limitations in technical design and the marginal clinical effect of methylprednisolone seen in the original multicenter studies have raised concern about this approach. Other medications, including Naloxone and Tirilazad, have also been examined; however, those studied did not achieve their primary endpoints. Most recently, the ganglioside, GM-1, has shown promise when administered in the subacute injury period, although primary endpoints were again not achieved. In general, most rehabilitation approaches are accepted in the field but specific aspects have not been tested for efficacy in the SCI population. Moreover, the duration of inpatient rehabilitation has dramatically decreased over the last 10 years, necessitating the development of cost-effective in-home therapies.
Functional electrical Stimulation (“FES”) has been used to restore certain functions following neural injury or disease. Examples include cochlear implants for restoration of hearing, stimulation of lower motor neurons to restore motor function including hand grasp and release, standing and stepping, breathing, and bladder emptying, and deep brain stimulation to treat the motor symptoms of Parkinson's disease (Grill and Kirsch, 1999; McDonald and Sadowsky, 2002). Each of these applications works by stimulating neural activity in existing neurons and muscles to restore control to systems where control has been compromised by injury or disease. However, FES has not been applied to reversing or altering disease progression or to promoting tissue regeneration or repair.
Locomotor training, such as on a treadmill, has been applied to motor incomplete patients (i.e., ASIA grade B or better) to enhance recovery of walking. Locomotor training can help such patients improve their walking speed and posture, and to relearn and maintain balance while walking. These improvements correlate well with corresponding improvements in muscle strength and in cardiovascular fitness, and are also believed to involve improved recruitment of existing, spared motor neurons. Locomotor therapy has been combined with partial body weight support (BWS) of up to 40%, to reduce the load borne by lower limbs during training, straighten walking posture, and assist certain aspects of gait such as swing and balance. BWS of greater than about 30-40% is generally thought to substantially limit any benefit of locomotor training to the patient.
FES therapy has been used in combination with locomotor or cycling training for motor incomplete patients. Field-Fote describes the combined use of FES with partial BWS and treadmill training, to improve over-ground walking ability in patients of ASIA grade C (Edelle C. Field-Fote, Arch. Phys. Med. Rehabil. 82: 818-24, (June 2001)). Patients were able to support at least 70% of their own body weight and were able to walk on a treadmill. Patients treated accordingly showed improved over-ground walking speed in the absence of BWS and FES, due to training effects on the musculoskeletal and cardiovascular systems. FES cycling has been described, for promoting recovery of leg strength and endurance in a motor incomplete patient (N. Donaldson et al., Spinal Cord 38:680-82 (2000)). FES cycling in the single subject resulted in increased leg muscle thickness and voluntary leg strength. However, only motor incomplete patients have been deemed to derive a benefit from FES therapy, or from locomotor training, or from a combination of the two, because the benefits of such therapy are linked to the training effects on existing, spared (i.e. undamaged) elements of the patient's neuromuscular system. Accordingly, since such training effects are obviated by the extreme injury and lack of sparing in motor complete patients, FES therapy and locomotor therapy have not even been tried with such patients.
A great need therefore remains for novel approaches to partially or completely restoring lost or impaired sensory and motor function in individuals suffering from disruptions of motor and sensory function due to damage of the CNS.